Over two dozen spliceosome proteins are involved in human diseases, also referred to as spliceosomopathies. WW domain-binding protein 4 (WBP4) is part of the early spliceosomal complex and has not been previously associated with human pathologies in the Online Mendelian Inheritance in Man (OMIM) database. Through GeneMatcher, we identified ten individuals from eight families with a severe neurodevelopmental syndrome featuring variable manifestations. Clinical manifestations included hypotonia, global developmental delay, severe intellectual disability, brain abnormalities, musculoskeletal, and gastrointestinal abnormalities. Genetic analysis revealed five different homozygous loss-of-function variants in WBP4. Immunoblotting on fibroblasts from two affected individuals with different genetic variants demonstrated a complete loss of protein, and RNA sequencing analysis uncovered shared abnormal splicing patterns, including in genes associated with abnormalities of the nervous system, potentially underlying the phenotypes of the probands. We conclude that bi-allelic variants in WBP4 cause a developmental disorder with variable presentations, adding to the growing list of human spliceosomopathies.

超过两打剪接体蛋白与人类疾病有关，也称为剪接体病。WW 结构域结合蛋白 4 (WBP4) 是早期剪接体复合体的一部分，之前在人类在线孟德尔遗传 (OMIM) 数据库中并未与人类病理学相关。通过 GeneMatcher，我们确定了来自 8 个家庭的 10 名个体患有严重的神经发育综合征，其表现各异。临床表现包括肌张力低下、整体发育迟缓、严重智力障碍、大脑异常、肌肉骨骼和胃肠道异常。遗传分析揭示了WBP4中五种不同的纯合功能丧失变异。对具有不同遗传变异的两个受影响个体的成纤维细胞进行的免疫印迹显示蛋白质完全丢失， RNA测序分析发现了共同的异常剪接模式，包括与神经系统异常相关的基因，可能是先证者表型的基础。我们得出的结论是， WBP4中的双等位基因变异会导致具有可变表现的发育障碍，从而增加了人类剪接病的数量。